Sterol O-acyltransferase 1 (SOAT1) is a key enzyme for cholesteryl ester biosynthesis. The objective of the present study is to investigate the role and underlying molecular mechanisms of SOAT1 in atherosclerosis. Our results indicated that SOAT1 was highly expressed in endothelial cells of atherosclerotic lesions in human patients with atherosclerosis and in apolipoprotein E deficient (ApoE(-/-)) mice fed with high fat diet (HFD). We established a model of atherosclerosis using ApoE and SOAT1 gene double knockout (ApoE(-/-)SOAT1(-/-)) mice. SOAT1(-/-) alleviated HFD-induced and spontaneously developed atherosclerotic lesions in ApoE(-/-) mice, accompanied with the reduced triglyceride (TG), total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C), while the enhanced high-density lipoprotein-cholesterol (HDL-C) in serum of ApoE(-/-) mice. SOAT1(-/-) decreased collagen accumulation in the lesions. SOAT1(-/-) reduced macrophage infiltration and suppressed inflammation in ApoE(-/-) mice fed with HFD, as evidenced by the decreased expressions of pro-inflammatory cytokines, including interleukin (IL)-1 beta, IL-6 and tumor necrosis factor alpha (TNF-alpha). Of importance, SOAT1(-/--)attenuated inflammation was along with the inactivation of beta-catenin and nuclear factor kappa B (NF-kappa B) ApoE(-/-) mice. Moreover, oxidative stress observed in ApoE(-/-) mice was inactivated by SOATI double knockout. In addition, expression levels of fatty acid synthase (FAS), stearoyl-CoA desaturase 1 (SCD1), protein convertase subtilisin/kexin type 9 (PCSK 9) and sterol regulatory element-binding protein-1c (SREBP-1c) were decreased in liver, peritoneal macrophages and abdominal aortas of SOAT1-knockout ApoE(-/-) mice. In contrast, SOAT1(-/-) displayed improved expressions of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and lipoxygenase (LOX)-alpha in liver, peritoneal macrophages and abdominal aortas of ApoE(-/-) mice. Of note, the in vitro study, oxidized low-density lipoprotein (ox-LDL) incubation reduced heme oxygenase (HO-1) expressions in human umbilical vein endothelial cells (HUVECs), which was improved by SOAT1 knockdown. Pretreatment of sn-protoporphyrin (SnPP), an important HO-1 inhibitor, abolished the role of SOAT1 inhibition in suppressing inflammation and abnormal cholesterol transportation. These results indicated that SOAT1 deficiency protected against atherosclerosis progression via inhibiting cholesterol transportation in ApoE(-/-) mice, which was, at least partly, dependent on HO-1 expressions. (C) 2018 Published by Elsevier Inc.